Diesters of dihydroxy-dithio-hexanediamide



Umted States Patent ce 3mm Patented Au 3?, 1965 3,261,457 KCN ON ON DREFHIERS 0F DHHYDRUXYdDlTHEQ- oononzornono rtoooenornclizenooou H 8 HEXANEDKAMHDE R 0 OX Milrlos Bodanszlry, Princeton, and John T. Sheehan, g

Middlesex, N.l., assignors to Win Mathiesan Chemical Corporation, New York, FLY a celebration of Virginia (A) No Drawing. Application Sept, 12, 1961, Ser. No. [1.- R=phenyl1 igg 495ifngow lgtent No.f smashes, gate;I Ngigg, S

a w iciisa ivision o. a ication er. 0. v Au fs, ices, new Patent Mi imalist, dated rm; iii 10 w ggizfillgisded and this application June 29, 19%, R00 0 OHCH CIhCI-IOO CR 2 Claims. or. ne -477 (B) This application is a division or" our application, Serial [Hz Rfphenyn No. 137,495, filed September 12, 1961, which in turn is a RCOOOHCHZOHCHOOR division of our application, Serial No. 47,129 filed August K911 J,9612960, and nowlatent No. 9,040,0a4, granted June 19, i; 3;}: fin 1 This invention relates to new chemical compounds and RIOOC C N NhLOOR more particularly to a new thiazolecarboxylic acid of the 20 (C) formula [III: R= henyl; R=C2H OH OH 17112 l i /S en o1r2on2en mono, W-CHCH2CH CH coon W H il HOOC-- -N N -COOH and salts thereof. Since the thiazolecarboxylic acid con- 0 0 tains both basic (i.e. amino) groups and carboxylic acid g HCOONH groups it is amphoteric in nature and thus forms salts l I with acids and bases. Although any acid or base may be HO I used in preparing the salts, the preferred acids are min- (v) eral acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid and S 7 1 S phosphoric acid. The preferred bases are ammonium hy- CHCH CH -OH droxide, alkali metal hydroxides (e.g., potassium hy- 39 l droxide and sodium hydroxide) and alkaline earth metal hydroxides (e.g., calcium hydroxide). In addition organic (VI) acids such as tartaric, citric and acetic acid, and organic bases, Such as alkylamines can be used To prepare Cornpounds A, succinaldehyde 1s 1nt er Th5 new thiazolacarboxyuc acid 0f this invention (as 40 acted with a CyHl'lld, StlCh as an alkali rnetal cyanide well as its salts) is useful as a precursor in the microbial e- Potasslum 'eyamde) and n acy1atmg.agen.t of preparation of the antibiotic thiostrepton. For this purelther the formula RCOX Wherem R 13 as pose it is addsd at a concgntmfion greatgl. than about herembefore defined and X is a halide, preferably chlo- 0.00l% (w./v.) to a nutrient medium containing a source The Feaetlen 1S conducted menfqueous medlum of carbon and energy, a source of assiinilable nitrogen and 4 Preferably m the l e results m w Preparation of a source or" assimilable sulfur (such as that described in ee f of me dlestel'e e zjs'dlhydroxy'hexene' US. Patent No. 2,982,689) when culturing Streptomyces dlmmle- Flompounds acid moiety ester azureus (Waksrnan, Collection No. 3705, Institute of eorrespendmg to the aeylatmg agent used Microbiology, New Brunswick, New lersey), for the pro- To Prepare P elther of the lsomers of auction of thiastrepton Compound A 18 treated with hydrogen sulfide, the reac- The vfinal products of this invention are prePal-ed by a hen preferably being conducted under basic COIldltlOIlS. series of'r'eactions using as the initial reactant succinalde- The reaetlen i m the prePaletlen of Qenlpeunds hyde. These reactions are shown schematically by the 'f fl 23'dlhydroxy'd'lthlehexanedlalmdei Where following equations. in these equations, R is a hydrol the aele molety the ester corresponds to the eel/lat carbon radical of less than ten carbon atoms, such as mg agent used m the first Step of the e lower alkyl (e.g., methyl, ethyl, propyl, butyl and heXyl), i are then reeneensed an ester of (6%, phsnyl, ptolyl and ogpxylyl), aralkyl (6% halopyruvrc acid of the rormula: XCH CGCGGR, wtolyl, phangthyl nd Z-phenyhpropyl), and cycloalkyl wherein X 1s halo, preferably brorno, and R is as herecyclophcmyi and cyclohflxyl); a is a Saturated iubefore defined. The reaction 18 preferably conducted hydrocarbon radical of less than ten carbon atoms, such in an Organ: solvent at an elevated temperature such as lower alkyl (e.g., methyl, ethyl, propyl and butyl). Each of the intermediates formed is a new compound of this invention. In addition to their use as intermediates, Compounds 1V and V can also be used as precursors in the production of thiostrepton.

as the reflux temperature of the solvent, and results in the preparation of Compounds C, wherein R and R are as hereinbetore defined.

Compounds C are then hydrolyzed in the usual mannet, as by treatment with a base, such as an alkali metal hydroxide (e.g., potassium hydroxide) to yield Compound IV, 2,2'(l,4-dihydroxytetramethylene)bis-(4-thiazolecarboxylic acid).

Compound 1V is then oxidized by treatment with sodium dichromate to give Compound V, 2,2-succinylbis(4- thiazolecarboxylic acid).

Compound V is then treated with ammonium formate at an elevated temperature and the resulting formyl derivative hydrolyzed, as by treatment with a mineral acid to yield one of the final compounds of this invention, Compound VI, 2,2-(1,4-diaminotetramethylene)bis(4- thiazolecarboxylic acid), which can be converted to a salt in the usual manner by treatment with the desired acid or base.

The following examples illustrate the processes of this invention (all temperatures being in Centigrade):

EXAMPLE 1 Benzoic acid, diester with 2,5-dihydrxyhexanedinitrile (I) A mixture of 30 g. of succinaldehyde, 750 g. of cracked ice, 44 g. of potassium cyanide and 94 g. (78 ml.) of benzoyl chloride is stirred for 1 hour. A milky semisolid separates from the reaction mixture. The mixture is filtered by suction, and the white solid residue washed with Water to give on drying about 15 g. solid 1. The original filtrate of the reaction mixture is extracted four times with 250 m1. portions of chloroform and the combined chloroform extract washed first with a solution containing 60 g. of sodium bicarbonate in 750 ml. of water and finally with three portions of 250 ml. of water. The chloroform extract is dried over anhydrous magnesium sulfate and after removing the latter and evaporating the solvent a residue of about 62 g. of heavy liquid remained. This residue on treatment with several volumes of hexane gives about 19 g. of solid II.

Solids I and II are separately treated with ether, from which extracts benzoic acid is recovered. The ether insoluble materials are treated with toluene on the steam bath and from these extracts a material, M.P. about 134- 136", separates.

Analysis.--Calcd for C H N O C, 68.96; H, 4.63; N, 8.04. Found: C, 68.89; H, 4.60; N, 7.93.

The toluene materials are then treated with dimethylformamide on the steam bath and solution is complete. On cooling a crystalline product melting at about 214 216 separates.

Analysis.-Found: C, 68.96; H, 4.81; N, 8.10.

The infrared spectra of both compounds are substantially the same.

EXAMPLE 2 Benzo ic acid, diester with 2,5 -dihydr0xydithi0hexanediamia'c (ll) Into a solution of 4.6 g. of the lower melting dinitrile obtained in Example 1 in 25 ml. of dimethylformamide containing 0.3 ml. of triethanolamine is bubbled hydrogen sulfide for six hours. After the addition of gas, the stoppered mixture is allowed to stand for 24 hours. The mixture is then treated with hexane and enough ethanol to make the mixture homogeneous. On standing a yellow solid slowly separates. Ultimately with scratching and further diluting with hexane and ethanol about 5 g. of product is obtained. The product is crystallized from large volumes of boiling ethanol and melts at about 203- 205.

AnalysisP-Calcd for C H N O S N, 6.73; S, 15.37. Found: N, 6.94; S, 15.40.

EXAMPLE 3 2,2'-(1,4-dihydr0iytctramethylene) bis(4-thiazolecarboxylic acid diethyl ester, diestcr with benzoic acid (III) A mixture of 2.5 g. of the dithioamide obtained in Example 2 and 2.5 g. of ethyl bromopyruvate in 100 ml.

EXAMPLE 4 2,2'- (1 ,4-dihydroxytetramethylene) bis (4-thz'az0lecarboxylic acid) (IV) 2.1 g. of the ester obtained in Example 3 is suspended in 50 ml. of absolute ethanol and 0.76 g. of potassium hydroxide in 5 ml. of absolute ethanol is added. While stirring at room temperature solution occurs within onehalf hour. The mixture is allowed to stand at room temperature overnight during which time a solid separates out. The insoluble material is filtered off and washed with ethanol. It is dissolved in 10 ml. of water and the aqueous solution then washed with ether and then acidified with 1 N hydrochloric acid. From the acid solution a precipitate slowly formed which is filtered off, Washed with water, and air dried to give about 1.0 g. of product, M.P. about 235-240. From the original mother liquor on evaporation a residue of about 1.6 g. of product is obtained. The residue is dissolved in 10 ml. of water and after washing the aqueous solution with ether, the aqueous solution is acidified with hydrochloric acid and the precipitate which forms filtered off. This material is benzoic acid. From this and the previous acid solution however, on cooling and standing about 0.2 g. additional product separates. Crystallized from boiling water, this compound separates out with one mole of water of crystallization which is lost on drying at The compound, 2,2'-(1,4-dihydroxytetramethylene)bis(4- thiazolecarboxylic acid), melts at about 240-242 (dec.).

Analysis.Ca1cd for CHHIZNZOGSZ: C, H, Found: C, 42.01; H, 3.95.

EXAMPLE 5 2,2'-succinyl bis(4-thiaz0lccarb0xylic acid) (V) 600 mg. of the diol acid obtained in Example 4 is suspended in 15 ml. of glacial acetic acid distilled from chromium trioxide, and 500 mg. of sodium dichromate in one-half a cubic centimeter of water is added to the suspension. The whole is kept at 100 for 2 hours. On cooling an insoluble material settles out. This material is filtered off and washed with a large amount of water and some dilute acetic acid. It weighs about 400 mg. After crystallization from dimethylformamide the 2,2- succinyl bis(4-thiazolecarboxylic acid) has a M.P. of about 284286 (dec.).

Analysis.-Ca1cd for C H N O S C, 42.36; H, 2.37. Found: C, 42.52; H, 2.90.

EXAMPLE 6 2,2- (1,4-diaminotetramethylene) bis-4-thiaz0lecarboxylic acid) (VI) 100 mg. of the diketo acid obtained in Example 5 is intimately mixed with 2.0 g. of ammonium formate in a Claisen type distilling flask. The flask is heated in an oil bath at an internal temperature of -155 until the initial foaming reaction subsides. The internal temperature is then gradually raised to -190 where it is kept for 3 hours. On cooling the residue is taken up in 25 ml. of water and any insoluble material removed via filtration. The filtrate is acidified with hydrochloric acid whereupon a precipitate separates out. It is filtered off and washed with water to yield a mixture of formyl derivatives. This mixture is heated under reflux with 5 ml. of concentrated hydrochloric acid for an hour. Hydrolysis proceeds and the mixture becomes homogeneous. On evaporation the residue obtained is dissolved in water from which VI slowly separates. It melts at about 5 235-237 (dec.). Calcd fOI' C12H1404N4S2C C, H, 4.12; N, 16.4; S, 18.7. Found: C, 42.5; H, 4.29; N, 16.4; S, 18.8. On Whatman No. 1 paper in a system of n-butanol-acetic acid-water (4: 1:1) the acid moves faster than cystine, R 0.0080.10.

EXAMPLE 7 2,2 I ,4-diam inotetram ethylene) bis( 4 -thiaz0lecarboxylic acid) dihydrochloride 40 mg. of 2,2'-(1,4-diaminotetramethylene)bis(4-thiazolecarboxylic acid) is dissolved in Warm N-hydrochloric acid. The dihydrochloride salt which forms slowly separates from solution and is removed by filtration.

EXAMPLE 8 2,2-(1,4-diaminotetramethylene)bis(4-lhiaz0lecarboxylic acid) ammonium salt 30 mg. of 2,2'-(1,4-diaminotetramethylene)bis(4-thiazolecarboxylic acid) is dissolved in an excess of ammonium hydroxide. Evaporation of the solvent yields the ammonium salt.

The invention may be variously otherwise embodied within the scope of the appended claims.

' References Cited by the Examiner UNITED STATES PATENTS 2,445,652 7/48 Whetstone 260-465.6 2,448,979 9/48 Hopff et a1. 260-465.6 3,040,054 6/62 Bodanszky et a1. 260-302 3,047,615 7/62 Nomine 260-476 3,049,557 8/62 Emrick 260-4106 3,065,240 11/62 Bodanszky et a1. 260-302 OTHER REFERENCES Erlenmeyer et al.: Helvetica Chimica Acta, vol. 27, pp.

LORRAINE A. WEINBERGER, Primary Examiner. NICHOLAS S. RIZZO, Examiner. 

1. THE DIESTER OF 2,5-DIHYDROXY-DITHIOHEXANEDIAMIDE WITH A HYDROCARBON CARBOXYLIC ACID OF LESS THAN ELEVEN CARBON ATOM SELECTED FROM THE GROUP CONSISTING OF SATURATED AND AROMATIC CARBOXYLIC ACIDS. 